The invention herein relates to certain types of medical treatments that use a laser-activated drug to slow down the growth of unwanted blood vessels in or behind the retina. This type of treatment can be used to treat a number of known eye and vision disorders, including:                (i) the “wet” form of macular degeneration, discussed in more detail below;        (ii) “proliferative diabetic retinopathy”, a term used when these types of problems occur in people who suffer from diabetes;        (iii) tissue responses that arise after an injury, infection, or inflammation, which are often given diagnostic labels, such as punctate inner choroidopathy, presumed ocular histoplasmosis syndrome, or multifocal choroiditis with panuveitis, as described in Wachtlin et al 2003.        
The medical term choroidal neo-vascularization is also used to describe unwanted blood vessel growth affecting the retina. The choroid is a specialized layer of structural tissue, near the back of the eye, which is interlaced with capillaries; vascular refers to blood vessels, and neo-vascular refers to the growth of new blood vessels that previously were not present in a certain tissue (this is distinct from re-vascularization, which refers to the re-growth of blood vessels that were disrupted by an injury).
The labels listed above overlap heavily, and often can be used interchangeably. For example, since the macula is part of the retina, any case of “macular degeneration” is also, by definition, a “retinopathy” (i.e., a pathological condition affecting the retina).
The discussion below focuses on “wet” macular degeneration as an exemplary form of the group of eye diseases and disorders that can be treated by photodynamic therapy, using a drug-and-laser combination as described below. This description is intended to be illustrative, rather than limiting, and the methods disclosed herein should improve the benefits and outcomes for at least some patients having any particular type of retinal problem that will require treatment by photodynamic therapy (PDT).
Since it is a descriptive label, the term macular degeneration can include any eye or vision disorder that involves degeneration of the macula, a small yellowish-colored circular area in the center of the retina. This includes degeneration that may be caused or aggravated by other factors, such as diabetes, a genetic disorder, a vitamin deficiency, senescence, etc. “Degeneration” implies gradual and progressive deterioration, but this can include degeneration following an injury, infection, etc. Review articles that describe the etiology, pathology, and current treatments for macular degeneration include Ambati et al 2003 and Zarbin 2004.
In primates (including humans), which are the only mammals that have maculas, the macula is crucial to clear vision. Because of how the eyes and brains of primates evolved interactively, the macula is the only portion of the retina that provides fine-resolution vision, and the remainder of the retina provides only coarse-resolution vision. This limits and controls the number of nerve impulses that must be rapidly processed by the brain to provide clear and rapid-response vision, and it reduces the burden on the retina to continually regenerate and recycle huge numbers of replacements for the rod and cone structures, which are the light-activated portions of retinal neurons.
However, since the macula is extremely complex and highly sensitive, it sometimes encounters serious problems. Because it is the only part of the retina that provides clear and sharp vision, if it degenerates seriously, people with macular degeneration often completely lose the ability to read, drive, recognize faces, or carry out numerous other tasks. Macular degeneration is the leading cause of blindness among the elderly, and its occurrence rates are increasing as the population ages, and as people eat more prepared and fatty foods, and fewer fruits and dark green vegetables.
Some cases that arise before the age of about 50 involve known genetic problems, including disorders and syndromes such as Stargardt's disease, Best's disease, Batten's disease, Sjogren-Larsson syndrome, cone-rod dystrophy, ovine ceroid lipofuscinosis, and various genetic defects involving problems with mitochondria or lysosomes; in addition, diabetics suffer from elevated risks of diabetic retinopathies, most of which involve degeneration of the macula. However, other than genetic or diabetic cases, the vast majority of macular degeneration cases do not become noticeable until someone is past the age of about 60. These cases often are called age-related macular degeneration (often abbreviated as AMD or ARMD).
Regardless of whether they are genetic, diabetic, or age-related, cases of macular degeneration are usually divided into two main categories, depending on the types of physiological symptoms they display. If abnormal blood vessel growth in and/or behind the macula is involved, that eye will be diagnosed as having the wet form (sometimes called the exudative form). If abnormal blood vessel growth is not involved, the term dry macular degeneration is commonly used. While genetic or diabetic cases of macular degeneration tend to cause relatively consistent and similar damage in both eyes, it is common for cases of age-related macular degeneration to be manifested as the wet form in one eye, and the dry form in the other eye.
Abnormal blood vessel growth, in and/or behind the macula, can severely disrupt clarity of vision. Because of evolutionary factors, the blood vessels that serve most of the retina actually sit on the anterior (front) side of the retina. As mentioned above, most of the retina provides only coarse-resolution vision, so this arrangement does not disrupt normal eyesight.
However, as mentioned above, primates evolved with retinas that are more complex and sophisticated than in other mammals, and in primates, a fine-resolution macular region evolved at the crucially important center of their retinas. In that small but crucial part of the retina, the placement of blood vessels is reversed, and the blood vessels are positioned behind the retina, in the layer known as the choroid.
Unfortunately, that arrangement causes the macula to become seriously disrupted, if new and unwanted blood vessels in the supporting choroidal layer begin growing and proliferating in uncontrolled ways, directly behind and beneath the macula. When someone begins to suffer from wet macular degeneration, it becomes obvious to that person, in a fairly rapid manner, that their central vision is becoming blurry, and losing clarity. The person becomes unable to focus clearly, even if he or she stops doing anything else and tries hard to look at something.
Although the causes of abnormal blood vessel proliferation in wet macular degeneration are not entirely understood, it is generally presumed that one or more triggering and aggravating factors begin to inflict damage and stress on the cells and membranes of the macula, and the macula responds to the damage and stress by sending out hormonal signals that will recruit more blood flow, to try to help the system. This is a conventional and normal physiological response, since increased blood flow to tissues that are releasing stress-induced hormones will, in most cases, provide more nutrients, and improve waste removal, both of which are usually beneficial.
However, because of the arrangement of the tissue layers and blood vessels behind the macula, an increase in blood vessel growth at that particular location causes more damage than good. That additional damage increases, rather than decreases, the level of stress on the macular tissues, and an out-of-control feedback loop (which can be called a “vicious circle”) begins to trigger even more aggressive blood vessel growth. Unwanted blood vessels begin growing even more rapidly, trying to cope with increasing levels of stress and damage in and around the macula, but the unwanted blood vessel growth makes the problems even worse. This leads to still more distress hormones being released by stressed and dying retinal cells, and those hormones trigger the growth of even more blood vessels.
As a result, wet (exudative) macular degeneration is highly aggressive. It spreads at relatively high rates, and it inflicts severe damage to the eyesight, often leading to functional blindness within a matter of months, compared to the slower progression of dry macular degeneration, which often takes years.
Even though the wet form of macular degeneration accounts for only about 5 to 15% of all cases of macular degeneration (estimates vary, because borderline cases often occur that are difficult to classify as either clearly wet, or clearly dry), it receives an inordinate amount of attention, compared to dry macular degeneration, for two reasons. First, the wet form is highly aggressive, and will spread rapidly, if not treated. The second factor is this: there is a form of treatment which, although not entirely satisfactory, offers at least some clear benefit to patients, by prolonging their eyesight for a span of months, or in some cases years.
This treatment is usually called “photodynamic therapy” (PDT). The drug that is most commonly used to carry out PDT is called verteporfin, sold under the trademark VISUDYNE by a joint venture between QLT Inc (www.qltinc.com) and Novartis Ophthalmics (www.novartis.com). Other drugs with similar activities and uses are being developed, including a drug referred to as SnET2 or rostaporfin, sold under the trademark PHOTREX by a company called Miravent. Accordingly, any references herein to verteporfin, or to laser-verteporfin treatment, are intended to be illustrative rather than limiting. It is believed and anticipated that the principles and teachings herein are likely to be equally applicable to PDT treatments using any specific type of PDT drug (including verteporfin, rostaporfin, etc., and any salts, analogs, and prodrugs thereof that may be used in PDT treatments), as can be evaluated by animal tests and/or human clinical trials using no more than routine testing.
Using verteporfin as an example, PDT treatment typically involves the following series of steps:
1. The drug is injected into the patient. It binds preferentially to low-density lipoproteins, which function as carriers, causing the verteporfin molecules to be transported preferentially to cells and tissues that are growing, including blood vessels that are actively growing behind the macula of a person with wet macular degeneration.
2. A period of time is allowed to pass, to ensure that the drug (bound to the LDL carrier molecules) has time to circulate through the patient, and into the growing capillaries in or behind his or her macula.
3. The patient is anesthetized, and a laser beam having a wavelength that will cause verteporfin to react is shone directly into the eye that is being treated.
4. When the laser beam hits the verteporfin molecules that are present in the thin-walled capillaries inside the retina, it causes a chemical reaction, which results in the verteporfin molecules breaking apart in a manner that causes them to release unstable and reactive molecules, usually called “oxygen free radicals” or “reactive oxygen species”.
5. The unstable and highly reactive oxygen radicals that are released by laser-activated verteporfin, inside the growing macular capillaries, attack the interior walls of the capillaries. This damages them, and effectively seals them off.
6. The damage to the growing macular capillaries, caused by the radicals released by the verteporfin inside the capillaries that were hit by the laser, helps to inhibit any additional blood vessel growth in the retina, for some period of time.
Additional information on PDT drugs and methods is available in several review articles, including Algvere et al 2002 and Hunt et al 2003. Still more information is available on QLT's website, www.qltinc.com, which lists published clinical studies, and a historical account by the National Eye Institute is available at www.nei.nih.gov/neitrials/static/study60.htm.
It should be noted that PDT is distinct from a treatment called photocoagulation, which uses a very thin laser beam to effectively burn, cauterize, and seal off one blood vessel at a time.
The efficacy, extent, and number of months of relief that will be provided by PDT treatment in different patients varies substantially, depending on factors that are not fully understood but that are believed to include: (i) the extent of the damage and stress that have already occurred inside a patient's retina, and (ii) the extent of unwanted blood vessel growth that has already occurred inside that patient's retina.
Under the current state of knowledge and technology, PDT treatment is not ideal, and needs to be improved. As stated in Schmidt-Erfurth et al 2003, “the potential and success of the approach are considerably compromised”. The known shortcomings of this treatment can be grouped into a number of categories, such as the following:
(1) Multiple treatments are required for most patients. For example, a recent review of a number of published articles describing clinical trials contained the statement, “Participants received on average five treatments over two years” (Wormald et al 2003). That number was merely an average, and many of those patients received larger numbers of treatments, in their struggle to keep their problem from getting worse.
(2) The results usually fall far short of being ideal, or restoring eyesight. When a series of multiple treatments is terminated, it is not because the patient has recovered, but because the physician and the patient both realize that still more treatments, costing multiple thousands of dollars each, will not provide any significant additional benefit.
(3) The net result of these treatments, in most patients, is that blood vessel growth and the resulting loss of eyesight is retarded for only a limited period of time, usually measured in months rather than years.
(4) When unwanted blood vessel growth begins to expand into an aggressive mode again, despite a series of PDT treatments, it usually signals that the end is approaching, and the patient will go functionally blind within a few months.
In addition to those “macroscopic” concerns that can be measured over patient populations, there are also concerns about the microscopic effects of verteporfin treatments, at the level of cells and molecules. Those factors include the following:
(a) Verteporfin blocks blood vessel growth by generating highly unstable, aggressive, and toxic “free radicals”, which then begin attacking the cells inside the capillaries where the drug was located when it was hit and activated, by the laser. However, at least some of those toxic free radicals are carried out of those capillaries, by continuing blood flow, during the seconds and minutes before the full response kicks in, before those free radicals have time to react with the cells that line the insides of the retinal capillaries. This means that highly unstable and aggressively toxic molecules are being distributed, by continuing blood flow, throughout other structures and blood vessels in the retina and eye, during the seconds and minutes immediately after the verteporfin is activated by the laser beam.
(b) Despite the use of low-density lipoproteins as carriers that can “enrich” (to some extent) the concentrations of verteporfin in actively growing capillaries as compared to old and normal capillaries, that delivery system is only semi-selective, and does not reach or even approach a level that would be regarded as “highly selective”. Low-density lipoproteins flow through every blood vessel and capillary; therefore, verteporfin-laser treatments cannot cleanly distinguish between unwanted capillaries that should be killed and sealed off, versus normal capillaries that are essential for providing nutrients to the retina and for removing waste metabolites from the retina.
(c) It has recently been reported (Schmidt-Erfurth et al 2003) that verteporfin-laser treatment stimulates, rather than suppresses, the release of hormones that increase blood vessel growth. Most notably, this includes a hormone called “vascular endothelial growth factor” (VEGF), discussed below. This hormonal response, which attempts to stimulate the growth of new blood vessels, is a normal and natural response in nearly any kind of tissue that must recover from a cut, bruise, broken bone, or other problem that disrupts blood supply.
The foregoing factors leads to two conclusions: (i) currently available PDT treatments are not ideal, or even close to ideal; and, (ii) their efficacy might be substantially improved, if methods or agents could be found for protecting desirable tissues, while focusing and targeting the damage more specifically toward the unwanted blood vessels.
For these reasons, a number of research efforts are underway, which are attempting to develop better methods for carrying out verteporfin-laser therapy. As one example, some ophthalmologists are studying the effects of injecting an anti-inflammatory steroid into a patient's bloodstream, as part of a PDT treatment. As another example, Spaide et al 2003 reported that if PDT treatment is followed immediately by an injection (directly into the vitreous humour, in the eye of a still-anesthetized patient) of an anti-inflammatory drug called triamcinolone acetonide (used today mainly for asthma and skin problems), the results of the PDT treatments appeared to be improved over the following months, when measured by periodic tests of visual acuity or retinal condition in treated patients.
In addition, methods are being tested for evaluating agents that can block certain specific types of growth hormones that are likely to be involved in abnormal blood vessel growth. One particular hormone that is receiving intense attention is called VEGF, which stands for “vascular endothelial growth factor”. “Vascular” refers to blood vessels, and “endothelial” refers to the types of cells that make up the walls of blood vessels. Therefore, a growth factor that specifically stimulates the growth of “vascular endothelial” cells, which create blood vessel walls, clearly is a prime suspect in unwanted blood vessel growth, in patients with wet macular degeneration. Therefore, antibodies or other agents (including VEGF “aptamers”) that can suppress the VEGF hormone (or that can occupy and block the cell-surface receptors that are activated by the VEGF hormone) are of great interest, among researchers and doctors studying ways of treating wet macular degeneration. Such agents are currently being tested in multi-center clinical trials, most of which are being sponsored by a company called Eyetech, which signed a licensing agreement with Pfizer in 2003. In various trials, anti-VEGF agents are being investigated by themselves, or in combination with verteporfin treatments. These trials are described in various articles such as Algvere et al 2002, and in a study authored by the Eyetech Study Group, published in Ophthalmology 110: 879-881 (May 2003).
Another hormone being studied closely is called pigment epithelium-derived factor (PEDF). Although this hormone normally helps suppress and control blood vessel growth, recent tests indicate that under certain conditions involving a protein called “mitogen-activated protein kinase” (MAPK), PEDF begins to act in combination with VEGF, so that both of them together have an even greater effect than VEGF alone, in stimulating blood vessel growth. These findings are discussed in Hutchings et al 2002, and in footnote 43 of Schmidt-Erfurth et al 2003.
It should also be noted that PDT treatments are occasionally used to treat certain types of eye problems that are not classified as wet (exudative) macular degeneration. For example, Wachtlin et al 2003 described the use of verteporfin to treat several types of problems that were grouped under the heading “inflammatory chorioretinal diseases”. Those problems included punctate inner choroidopathy, presumed ocular histoplasmosis syndrome, multifocal choroiditis with panuveitis, and “other inflammatory conditions”. The results indicated that verteporfin treatments for those conditions tended to perform better, and more effectively, than verteporfin treatments for wet macular degeneration. That result should not be surprising, since those types of inflammations tend to arise after a one-time infection, injury, or other insult that usually can be treated and resolved. By contrast, wet macular degeneration arises when the macula is suffering from some type of ongoing stress that causes the surrounding system to respond by trying to provide the area with additional blood supply.
Finally, it must also be noted that PDT treatments are very expensive. Internet postings state that each dose of verteporfin, used in a single treatment, costs more than $1000. That is the cost for that drug only, and it does not include any additional costs for physician or anesthesiologist services, clinic or hospital costs, or any other medication or service costs, all of which add up to multiple thousands of dollars per treatment.
Accordingly, despite progress in efforts to develop improved PDT treatments, there remains a critical need for ways to increase the safety and efficacy of such treatments.
Information On Zeaxanthin And Lutein
Because zeaxanthin is involved in this invention, background information needs to be provided on it, and on a related and similar compound called lutein. Both compounds are carotenoids, created naturally in plants and a few types of bacteria. Like other carotenoids, they cannot be synthesized by animals, and must be ingested as part of the diet.
The molecular structures of zeaxanthin and lutein (along with beta-carotene, for comparative purposes) are illustrated in FIG. 1. Like many other carotenoids, zeaxanthin and lutein are effective in absorbing ultraviolet light, and in neutralizing (“quenching”) destructive compounds called radicals. Those are the primary functions of all carotenoids in plants, and in bacteria that must withstand direct sunlight for long periods of time.
However, unlike other carotenoids, zeaxanthin and lutein play special roles in the eyes of primates, including humans. They are the two carotenoid pigments that give the macula a yellowish tint; therefore, zeaxanthin and lutein are often referred to as the two “macular pigments”.
The roles and activities of zeaxanthin and lutein, in human maculas, are described in articles such as Handelman et al 1988, Schalch 1992, and Snodderly et al 1995, and in U.S. Pat. No. 5,747,544 (Garnett et al 1998, which discloses a method of using zeaxanthin to treat or prevent macular degeneration) and Reissue patent Re-38,009 (Garnett et al 2003, which covers zeaxanthin formulations for human ingestion).
A number of factors can be used to point out similarities and differences between: (1) the roles and involvement of lutein and zeaxanthin in plants, where photosynthesis is crucial, and (2) their roles and involvement in animals, where photosynthesis does not occur and is irrelevant. Those factors can be gleaned from various disparate items of prior art; however, they have never been adequately correlated and analyzed in the manner provided below, and numerous skilled researchers and physicians who specialize in working with human health and eyesight apparently have failed to recognize or appreciate the existence, relationships, or significance of these factors. Therefore, these insights and correlations are not conceded to be prior art against this invention, and they are discussed in the Detailed Description section, below.
It should also be noted in particular that zeaxanthin and lutein are classified and regarded as anti-oxidants. This is highly important, because the literature published by QLT PhotoTherapeutics and Novartis Ophthalmics (which jointly sell verteporfin under the trademark VISUDYNE) contains a clear and explicit warning: “Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, beta-carotene, ethanol, formate and mannitol, would be expected to decrease VISUDYNE activity.”
Zeaxanthin and lutein fall squarely within that category; they are directly related to beta-carotene, and they clearly “quench active oxygen species or scavenge radicals”.
Therefore, that published warning teaches directly away from the use of zeaxanthin to improve the results of verteporfin therapy. As an illustration of this principle, when the patient described below in Example 1 informed his ophthalmologist that he (the patient) was taking zeaxanthin, the ophthalmologist advised the patient, quite reasonably and in full accord with the warning that was published by the makers of verteporfin, that he (the patient) should stop taking zeaxanthin, since it might interfere with the treatment. However, the patient continued taking it anyway, against the advice of his doctor, and he received unexpectedly good results from the treatment, as described below.
Accordingly, one object of this invention is to disclose and provide a method of improving the results, efficacy, and benefits of photodynamic therapy using verteporfin or other drugs that create radicals or release toxins when activated by light, among patients with “wet” macular degeneration or other retinal problems.
Another object of this invention is to disclose and provide a non-invasive pre-treatment regimen, using orally-ingested zeaxanthin at a dosage and for a span of time that will result in a detectable increase in “macula pigment optical density” (MPOD), prior to photodynamic therapy, to increase the safety, efficacy, and benefits of the treatment.
Another object of this invention is to disclose that oral ingestion of at least 3, preferably at least 10, and even more preferably at least 20 mg/day of zeaxanthin, for a span of at least about a week and preferably 2 weeks or more, can improve the efficacy and benefits of photodynamic therapy, among patients with “wet” macular degeneration or similar retinal problems.
Another object of this invention is to disclose that orally-ingested zeaxanthin, taken as a “pre-loading” step prior to a PDT treatment, can improve the efficacy and benefits of the PDT treatment.
These and other objects of the invention will become more apparent through the following summary, drawings, and detailed description.